Diffuse large B-cell lymphoma combined with hyperlactatemia presents high mortality: case report and literature review

Abstract

Diffuse large B-cell lymphoma (DLBCL) can present with hyperlactatemia or even lactic acidosis (LA) as a rare but often underrecognized complication among hematologists. Patients diagnosed with DLBCL complicated by LA generally exhibit high mortality and a poor prognosis, even with therapeutic intervention. This report details two cases of DLBCL concurrently presenting with LA and provides a literature review. Our analysis of 19 published studies revealed a survival advantage in patients with an initial lactate levels of 5–14.9 mmol/L compared to those with levels of 15–24.9 mmol/L. Furthermore, the maximum lactate level correlated with survival, with higher values predicting shorter survival times. For type B LA, early initiation of chemotherapy-based treatment significantly improved patient survival compared to other treatment approaches (P = 0.026). Adjunctive treatments such as sodium bicarbonate, thiamine, and vitamin B may also be beneficial. Careful attention should also be paid to avoiding medications that can increase lactate levels.

Keywords

diffuse large B-cell lymphoma / hyperlactatemia / lactic acidosis

1 Introduction

Diffuse large B cell lymphoma (DLBCL) is a common malignant lymphatic disease, accounting for approximately 37% of B cell lymphomas [1]. The standard treatment for DLBCL generally involves the R-CHOP regimen (rituximab, cyclophosphamide, vincristine, doxorubicin, and glucocorticoids) after excluding contraindications. Hyperlactatemia is a rare complication observed in lymphoma, defined as a lactate concentration of 2–5 mmol/L. Lactic acidosis (LA), a more severe form, is characterized by a lactate concentration exceeding 5 mmol/L with a pH below 7.35. LA is categorized into three types: A (tissue hypoxia type), B (not related to tissue hypoxia) and D (related to D-lactic acid). Type A is usually caused by tissue hypoxia due to hypoperfusion, severe hypoxemia, or anemia. Type B can be further subdivided into three subtypes: B1 (associated with an underlying disease such as decreased clearance due to liver dysfunction or the Warburg effect in malignancy), B2 (associated with toxins or drugs), and B3 (inborn errors of metabolism) [2,3]. Type D LA results from excessive production of D-lactic acid by proliferating intestinal bacteria and is commonly observed in patients with short bowel syndrome or other forms of gastrointestinal malabsorption [4]. During malignant transformation, cancer cells accelerate glycolysis, producing large amounts of lactic acid that exceeds the body’s clearance capacity, leading to its accumulation [5]. Hematological malignancies are more frequently associated with this form of LA compared to solid tumors, such as leukemia and lymphoma [6]. Clinically, patients may present with both type A and type B LA, complicating the differentiation between them. In this study, we report two cases of DLBCL with LA with an extremely poor prognosis. These cases prompted a comprehensive review of the relevant literature.

2 Case report

2.1 Patient 1

A previously healthy 60-year-old male presented with dysphagia for 3 weeks, fever (maximum temperature 38.9 °C) for 2 weeks following tonsillectomy, and blurred vision for 1 week. At admission, his vital signs were within normal limits. Physical examination revealed no palpable superficial lymphadenopathy, but a thick white moss was observed in the pharynx. Pathological examination of the right tonsil mass confirmed DLBCL (non-GCB type) with MYC/BCL-2 double expression, showing BCL-6 (80%+), Ki-67 (90%), BCL-2 (90%+) and c-MYC (70%+). FISH analysis ruled out double-hit lymphoma. Bone marrow cytomorphology indicated lymphoproliferative disorder. Flow cytometry detected a small number of monoclonal B lymphocytes, suggesting a possible mature large B cell lymphoma, characterized by bright CD19 (+), HLA-DR (+), FMC7 (+), CD22 (+), cytoplasmic κ (+), CD20 (+), CD11c (+) and cKi67 (55%). Chromosomal examination revealed abnormalities: 78-84, XX, +X, +X, add(Y)(p11)*2, −1, der(1), der(2), +del(2)(p13), −3, der(3), der(4), −6, add(6)(p21)*2, del(6)(q21), +7, −8, −8−9, −10, −11, add(11)(p15), add(12)(p13), der(12), ins(13;?)(q14;?), −14, −14, add(14)(q24), −15, −15, −16, −17, der(17), −18, der(18), i(18)(q10), +19, +20, +20, +20, −21, −22, −22, +r[CP10]/46,XY[10]. Next-generation sequencing (NGS) revealed mutations in MYD88, ETV6, NCOR2, PIM1, TET2, FOXC1, GRHPR, HIST1H1E, IGLL5, IRF4, MPEG1, OSBPL10, PIM2, and TMSB4. Positron emission computed tomography (PET-CT) revealed bilateral adrenal soft tissue masses with increased FDG uptake (SUV_max = 39.1, D_max = 55 mm), multiple lymph nodes in the mediastinum and right lung hilar (SUV_max = 20, D_max = 21 mm), retroperitoneal and diaphragmatic pedicle areas (SUV_max = 47.9, D_max = 27 mm), left pararenal nodular lesions (SUV_max = 12.5, D_max = 12 mm), irregular hyperdense lesions in the para-splenic area (lymphoma with adrenal gland invasion? SUV_max = 35.9); a hypodense lesion in the peritoneal area adjacent to the lower right posterior hepatic lobe (SUV_max = 19.1), localized soft tissue thickening adjacent to the left 11th posterior rib in the abdominal wall (SUV_max = 29), increased FDG uptake in the right lateral oropharyngeal wall (SUV_max = 21.8), and diffuse and heterogeneous FDG uptake in bone and bone marrow with localized nodular lesions (SUV_max = 9.9). On admission, the patient presented with mild liver function abnormalities (AST 97 U/L, ALT 51 U/L, GGT 94 U/L), while complete blood count, renal function, and coagulation parameters were within normal limits. Blood cultures from both arms were negative. Procalcitonin (PCT) levels were elevated at 1.59 ng/mL, and C-reactive protein (CRP) levels were 251.5 mg/L. Fungal antigen and galactomannan tests were negative, and virus tests showed no abnormalities. Based on examination and test results, the fever was primarily attributed to pharyngeal infection, although tumor-related fever could not be ruled out.

The patient was diagnosed with DLBCL (stage IVB, MYC/BCL-2 double expressor), with an IPI score of 3 (high-intermediate risk) and an age-adjusted IPI (aaIPI) score of 3 (high risk). After admission, imipenem and cilastatin sodium, micafungin, and contezolid were initiated for infection control. On the second day (D2) of admission, blood gas analysis revealed a lactate concentration of 3.70 mmol/L, pH 7.479, PaO₂ 66.4 mmHg, PaCO₂ 26.5 mmHg, SpO₂ 92.5%, and an anion gap (AG) of 20.42 mmol/L. In this patient, hyperlactatemia was potentially attributed to both type A (mild hypoxemia) and type B (high tumor burden). Severe infection such as sepsis may lead to both type B LA (early phase) and type A LA (shock phase) [3], but this etiology was considered less likely in this patient given his focal and controlled infection and normal blood pressure. The patient received dexamethasone (15 mg/day), and R-CHOP chemotherapy was planned following complete infection control. Following dexamethasone treatment, the patient’s body temperature stabilized, and symptoms improved compared to admission. However, on the fourth day of admission, the patient experienced a sudden, progressive decrease in peripheral oxygen saturation. SpO₂ was 80%–84%, which transiently improved to 94%–96% with oxygen supplementation at 10 L/min via face mask. Blood pressure remained 140/88 mmHg. Laboratory findings included: WBC 24.71 × 10⁹/L, PLT 48 × 10⁹/L, HGB 126 g/L, PT 16.9 s (reference range: 11.0–13.7 s), APTT 44.2 s (reference range: 31.5–43.5 s), D-Dimer 20 μg/mL, Fibrinogen 6.67 g/L, AST 313 U /L, ALT 47 U/L, GGT 77 U/L, and anion gap 28.62 mmol/L. Blood gas analysis further confirmed severe LA, with a lactate concentration of 17 mmol/L, and a pH of 7.225 (Fig. 1). The patient’s family declined mechanical ventilation and further ICU management. Respiratory stimulants were administered, leading to temporary stabilization. Subsequently, the patient experienced a rapid decline in blood oxygen saturation and blood pressure, which culminated in cardiac arrest. Despite vasopressors (dopamine) administration and cardiopulmonary resuscitation (CPR) efforts, the patient succumbed.

2.2 Patient 2

A 74-year-old man presented with a 2-month history of back pain. Physical examination was unremarkable. Laboratory findings included: WBC 21.96 × 10⁹/L, HGB 117 g/L, PT 13.4 s (reference range: 11.0–13.7 s), fibrinogen 4.38 g/L, AG 20.49 mmol/L, ALP 155 U/L, LDH 639 U/L, CRP 183.7 mg/L, PCT 3.11 ng/mL, IL-6 10.65 pg/mL, β2-MG 4.65 mg/L. Concurrently, arterial blood gas analysis revealed a lactate of 10.10 mmol/L, pH 7.380, PaO₂ 38 mmHg, PaCO₂ 30 mmHg, SpO₂ 53.5%. A puncture biopsy of the right scapula confirmed DLBCL (non-GCB type) with BCL-2/MYC double expression. Immunophenotyping showed SMARCA4 (+), Ki-67 (80%+), CD3 (T cell, +), CD20 (+), MUM1 (70%+), BCL-2 (80%+), Pax-5 (+), c-MYC (30%+), CD5 (T cell, +), and BCL-6 (30%+). FISH analysis indicated MYC negativity, thereby ruling out double-hit lymphoma. PET-CT results revealed widespread metabolic abnormalities, including: multiple mass-like and nodular lesions with increased FDG uptake in the right lung (SUV_max = 28.7, S_max = 44 mm × 36 mm), diffuse pulmonary involvement characterized by dense opacities, ground-glass opacities, and honeycomb opacities in both lungs (SUV_max = 5.7), lymphadenopathy in the mediastinal 2 L region and right cardiophrenic angle (D_max = 11 mm, SUV_max = 11.2), a mass at the right cardiac border (SUV_max = 28.9, S_max = 83 mm × 37 mm), a mass posterior to the inferior vena cava in the posterior mediastinal diaphragm (SUV_max = 29.5, S_max = 60 mm × 37 mm), masses in left kidney (SUV_max = 27.9, S_max = 61 mm × 60 mm) and left adrenal gland (SUV_max = 28.2, S_max = 37 mm × 27 mm), lymphadenopathy in the right diaphragmatic pedicle and retroperitoneal areas (D_max = 10 mm, SUV_max = 11.1), right scapular mass (SUV_max = 28.3), sacral and left iliac masses (SUV_max = 34.5) and no abnormal FDG uptake was noted in bone and bone marrow.

Overall, the patient was diagnosed with DLBCL (Stage IVB, BCL-2/MYC double expression) with an IPI score of 5 and an aa-IPI score of 3, both indicating high risk. The patient’s LA was attributed to both type A (respiratory failure) and type B (high tumor burden). Due to the relationship between the respiratory failure and pulmonary tumor infiltration, reducing tumor burden was identified as the critical therapeutic objective for this patient. The patient was administered a Pola + R + CHP regimen, which included polatuzumab vedotin (90 mg on Day 1), rituximab (640 mg on Day 1), cyclophosphamide (1.2 g on Day 2), doxorubicin (20 mg on Day 2), and methylprednisolone (80 mg on Days 1–6). Despite this aggressive therapeutic intervention, the patient’s respiratory distress progressively worsened, and he ultimately succumbed to respiratory failure on the sixth day of admission.

3 Discussion

Under sufficient oxygen conditions, DLBCL cells tend to undergo aerobic glycolysis, metabolizing glucose to lactate for rapid energy production. This process results in the substantial accumulation of lactate within the tumor microenvironment (TME), thereby inducing acidosis. The acidified TME promotes tumor progression through several mechanisms: it degrades the extracellular matrix, promoting tumor cell invasion into surrounding tissues [7]; the acidic conditions inhibit the function of key immune cells such as T cells and natural killer (NK) cells, which facilitates immune escape [8]; and acidosis may impair the efficacy of certain chemotherapeutic drugs [9]. Extremely high lactate levels can trigger LA, directly leading to multiple organ dysfunction. This can lead to a rapid decline in the patient’s physical status, rendering them unable to tolerate standard-intensity chemotherapy regimens and ultimately contributing to a poor prognosis.

Here we present two cases of DLBCL with LA, both of whom expired shortly after admission. Both patients were admitted to the hematology department with advanced-stage disease after a prolonged diagnostic phase, a common challenge in lymphoma management. Case 1 exhibited high proliferative activity, with a Ki-67 index of 90% and a maximum PET-CT SUV of 47.9; this was associated with type B LA through the Warburg effect. Infection may also have partly contributed to type A LA. Case 2 was characterized by a high tumor burden with multiple large masses, especially a 61 mm × 60 mm large mass in the left kidney and multiple masses in the lung with a maximum size of 44 mm × 36 mm. The kidney is the second most important organ for lactate metabolism after the liver. Renal involvement might impair lactate clearance, resulting in systemic lactate accumulation and exacerbating type B LA. The lungs are the primary site of gas exchange, and impaired pulmonary function can induce tissue hypoxia, resulting in type A LA. Therefore, we propose that LA in both patients was caused by both type A and type B mechanisms, a common clinical scenario. The poor prognosis of these two patients prompted a comprehensive literature search to identify methods for improving prognosis.

A comprehensive search strategy, employing the terms “DLBCL and lactic acidosis,” “DLBCL and hyperlactatemia,” “lymphoma and lactic acidosis,” and “lymphoma and hyperlactatemia” was conducted across PubMed, Web of Science, and Embase, yielding 30 articles. Among these, one article was in Russian, one in Japanese, seven were unrelated to DLBCL, and two were excluded due to insufficient specification of non-Hodgkin lymphoma (NHL) subtype. Eventually, 19 articles met the inclusion criteria. The flow chart of the search process is presented in Fig. 2. Basic characteristics of the 19 patients are summarized in Table 1.

Of the 19 patients diagnosed with LA, 8 had liver involvement and 1 had renal involvement. This phenomenon is consistent with the crucial role of the liver and kidney in lactate clearance. This highlights the increased importance of monitoring lactate levels in lymphoma patients with liver and renal involvement.

Studies investigating the Warburg effect in lymphoma patients in the ICU have identified a correlation with increased tumor burden and a higher 1-year mortality rate [29]. Consistently, survival analysis of the 19 patients showed a poor prognosis for DLBCL patients with hyperlactatemia, with the majority succumbing without primary disease treatment following the initial diagnosis. Patients with higher initial or maximum lactate concentrations tended to have a poorer prognosis, despite the lack of statistical significance (Fig. 3A and 3B).

Among the 19 patients, 11 underwent chemotherapy [12,14–16,18–21,23–25]. Despite a declining trend in lactate concentrations among those receiving chemotherapy, seven patients succumbed, with four during initial treatment and three due to subsequent DLBCL progression. Patients receiving chemotherapy-based treatment demonstrated a significant advantage in overall survival (OS) compared to other treatments (P = 0.026) (Fig. 3C). A significant early survival benefit was observed at 30 days for chemotherapy versus other treatments (P = 0.026) (Fig. 3D). Although this may reflect a selection bias toward patients in better general condition who could tolerate early chemotherapy, it also suggests the importance of early initiation of chemotherapy in improving prognosis.

Of note, two patients received thiamine combined with chemotherapy [16,21], one received thiamine alone [22], and one received no treatment [13]. Among the three patients treated with thiamine, two survived—including one who received thiamine as monotherapy. This suggests a potential benefit of thiamine. Thiamine deficiency has been associated with type B LA due to its role as a cofactor for pyruvate dehydrogenase, which facilitates the conversion of pyruvate to acetyl-CoA. Insufficient thiamine levels lead to rapid pyruvate conversion to lactate in tumor cells [30]. Given that lymphomas have significantly increased energy demands, the accelerated glycolytic flux can precipitate thiamine deficiency [31]. Supplementing thiamine serves as a metabolic rescue therapy. By providing the essential cofactor, it restores the primary energy-producing pathway, redirecting pyruvate metabolism away from lactate generation and toward efficient ATP production, thereby correcting hyperlactatemia. This intervention provides critical time for primary therapies (such as chemotherapy for DLBCL) to take effect, as metabolically stabilized patients are better able to tolerate and respond to treatment. Additionally, vitamin B was also incorporated into the treatment in one case. Vitamin B supplement not only impacts nutrient metabolism but also contributes to anti-inflammatory processes. Cao et al. observed that alterations in vitamin B metabolism influence disease progression in DLBCL patients [32].

The most direct method to correct LA is rapid lactate elimination, but current methods are limited. Continuous renal replacement therapy (CRRT) can be an effective option for facilitating lactate clearance. CRRT was used in five patients, resulting in varying degrees of lactate reduction. However, the utilization of CRRT did not significantly improve prognosis in our study (Fig. 3E), which may need more investigation. Alkalization therapy has also been reported as effective in reducing lactic acid in tumor-induced hyperlactatemia [33]. Sodium bicarbonate is frequently used; however, the efficacy of sodium bicarbonate treatment remains uncertain. This treatment may result in CO₂ accumulation and subsequent intracellular acidosis, as the lungs may not adequately and promptly clear CO₂ from tissues promptly [34]. Urease can convert endogenous urea into bicarbonate anion and may help correct acidosis [35]. Oral HCl absorbers, such as veverimer, can bind HCl in the gastrointestinal tract and increase systemic bicarbonate levels [36]. To reduce CO₂ production, buffers such as THAM (tris-hydroxymethyl-aminomethane) and Carbicarb (a 1:1 mixture of sodium carbonate and sodium bicarbonate) have been developed [37]. Inhibition of NHE1 (sodium-hydrogen exchanger 1) has been shown to reduce cellular injury [38]. Dopamine, acetylcholine, and nitroglycerin can independently enhance microvascular perfusion, reduce hyperlactatemia, and even improve prognosis, irrespective of systemic hemodynamics [39].

Many medications can lead to type B2 LA, several of which are frequently used in hematology, including nonsteroidal anti-inflammatory drugs (NSAIDs), sulfamethoxazole, linezolid, entecavir, ganciclovir, metformin, fludarabine, and carboplatin. Particular attention should be paid to these medications to prevent the exacerbation of LA. Other medications, including epinephrine, antituberculosis agents, opioids, albuterol, and diazepam, can also induce type B LA and should be used with caution [40].

For type A LA, necessary symptomatic supportive therapies should be combined with etiological therapies. It is essential to ensure adequate alveolar ventilation and tissue perfusion. For instance, in cases involving cardiogenic factors, normal cardiac function should be restored as promptly as possible. Similarly, antibiotics should be administered to patients with sepsis.

4 Conclusions

LA is a rare, severe, and urgent complication of DLBCL, necessitating prompt diagnosis and treatment due to its high mortality and poor prognosis. Currently, the primary strategy for managing type B LA involves targeted therapy combined with chemotherapy to reduce tumor burden and consequently decrease lactate production. Supplementation with agents such as thiamine, which addresses lactate production resulting from deficiency, and vitamin B family medications may offer benefits. Careful attention should be paid to avoiding medications that can increase lactate levels. For type A LA, necessary symptomatic supportive therapies combined with etiological therapies are important. Nevertheless, despite employing even the most efficacious chemotherapy regimens, saving the lives of most patients remains challenging, as DLBCL patients presenting with hyperlactatemia continue to exhibit a high mortality rate. Therefore, unexplained hyperlactatemia should be promptly identified and managed.

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